tbuckley/cabot-search huggingface dataset:
Discoidin Domain Receptor-Driven Gene Signatures as Markers of Patient Response to Anti–PD-L1 Immune Checkpoint Therapy
Authors: Sungyong You, Minhyung Kim, Xen Ping Hoi, Yu Cheng Lee, Li Wang, David Spetzler, Jim Abraham, Dan Magee, Prerna Jain, Matthew D Galsky, Keith Syson Chan, Dan Theodorescu
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Anti–programmed cell death 1 (anti–PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to predict nonresponders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti–PD-1 resistance in animal models; therefore, we sought to investigate whether this gene family may provide ICT response prediction. Methods We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (BCa) models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa–The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR-driven signatures to predict ICT response was evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided. Results DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell–inflamed phenotype, whereas DDR1high BCa exhibited a non–T-cell–inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P &amp;lt; .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets. Conclusions These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response.
Addressing Common Misuses and Pitfalls of <i>P</i> values in Biomedical Research
Authors: Ming Wang, Qi Long
Journal: Cancer Research (2022)

Abstract In recent years, there has been a growing recognition that P values, albeit useful in reporting data analysis results, have often been misused or misinterpreted in biomedical research. The emergence of big health data such as genomics data and electronic health records, sometimes combined with inadequate experimental design, has exacerbated this problem, which has become a major cause of the ongoing crisis in reproducibility in biomedical research. We aim to shed light and raise awareness of common misuses and pitfalls of P values and discuss potential mitigation strategies that leverage state-of-the-art statistical methods. The best practices always start with a sound study design including a robust data collection strategy to minimize data bias and a carefully thought-out analysis plan that can address potential misuses and pitfalls of P values. We highly encourage biomedical researchers to engage and involve statisticians from the very beginning of their studies.
Investigating Morphologic Correlates of Driver Gene Mutation Heterogeneity via Deep Learning
Authors: Andrew H. Song, Drew F.K. Williamson, Faisal Mahmood
Journal: Cancer Research (2022)

Abstract Despite the crucial role of phenotypic and genetic intratumoral heterogeneity in understanding and predicting clinical outcomes for patients with cancer, computational pathology studies have yet to make substantial steps in this area. The major limiting factor has been the bulk gene–sequencing practice that results in loss of spatial information of gene status, making the study of intratumoral heterogeneity difficult. In this issue of Cancer Research, Acosta and colleagues used deep learning to study if localized gene mutation status can be predicted from localized tumor morphology for clear cell renal cell carcinoma. The algorithm was developed using curated sets of matched hematoxylin and eosin and IHC images, which represent spatially resolved morphology and genotype, respectively. This study confirms the existence of a strong link between morphology and underlying genetics on a regional level, paving the way for further investigations into intratumoral heterogeneity. See related article by Acosta et al., p. 2792
Correction: Functional Genomic Analysis of <i>CDK4</i> and <i>CDK6</i> Gene Dependency across Human Cancer Cell Lines
Authors: Zhouwei Zhang, Lior Golomb, Matthew Meyerson
Journal: Cancer Research (2022)

In the original version of this article (1), there was an error in Fig. 3D. Specifically, the crystal violet staining images for CDK4 KO, CDK6 KO, and Dual KO were incorrectly arranged between Set1 and Set2. This error was inadvertently introduced during the final proofing stage for the manuscript. The correct images have been provided, and the error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Breaking Insights| August 03 2022 Highlights from Recent Cancer Literature Author & Article Information Online ISSN: 1538-7445 Print ISSN: 0008-5472 ©2022 American Association for Cancer Research2022American Association for Cancer Research Cancer Res (2022) 82 (15): 2659–2660. https://doi.org/10.1158/0008-5472.CAN-82-15-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record August 3 2022 Citation Highlights from Recent Cancer Literature. Cancer Res 1 August 2022; 82 (15): 2659–2660. https://doi.org/10.1158/0008-5472.CAN-82-15-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search As part of the Glioma Longitudinal Analysis (GLASS) Consortium aimed at understanding glioma evolution and therapeutic vulnerabilities, Varn and colleagues analyzed over 300 glioma patients wild-type or mutant for isocitrate dehydrogenase (IDH-wt and IDH-mut, respectively), with RNA and DNA sequencing data available at multiple time points. Longitudinally, the authors discovered that the IDH-wt gliomas switched from the classical subtype to the mesenchymal subtype, whereas IDH-mut gliomas remained proneural. Moreover, IDH-wt gliomas showed increases in oligodendrocytes, neural signaling pathways, and invasion. Whereas IDH-wt glioma typically present with CDKN2A deletions, IDH-mut tumors tended to acquire deletions in CDKN2A or amplifications of CCND2 at recurrence. Myeloid cells were also implicated in driving the mesenchymal subtype of glioma at recurrence, potentially through myeloid-tumor interactions such as those mediated by oncostatin M and its receptor. Expert Commentary: Diffuse gliomas undergo several changes in cell state and molecular... You do not currently have access to this content.
Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation
Authors: Brett I. Bell, Justin Vercellino, N. Patrik Brodin, Christian Velten, Lalitha S.Y. Nanduri, Prashanth K.B. Nagesh, Kathryn E. Tanaka, Yanan Fang, Yanhua Wang, Rodney Macedo, Jeb English, Michelle M. Schumacher, Phaneendra K. Duddempudi, Patrik Asp, Wade Koba, Shahin Shajahan, Laibin Liu, Wolfgang A. Tomé, Weng-Lang Yang, Richard Kolesnick, Chandan Guha
Journal: Cancer Research (2022)

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects.
Correction: Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation
Authors: Fan Zhang, Lihong Lou, Bo Peng, Xiaotian Song, Ofer Reizes, Alexandru Almasan, Zihua Gong
Journal: Cancer Research (2022)

In the original version of this article (1), there was an error in Fig. 6D. Specifically, the image used to show the Coomassie blue staining was the same as the image used in Fig. 6E for the +IR condition. The correct figure has been provided, and the error has been corrected in the latest online HTML and PDF version of the article. The authors regret this error.
Perioperative ctDNA-Based MRD Detection in NSCLC— Letter
Authors: Shixiong Wei, Xinliang Gao, Mingbo Tang, Jialin Li, Kewei Zhang, Linan Fang, Jingyao Dong, Wei Liu
Journal: Clinical Cancer Research (2022)

We have read with great interest about Xia and colleagues’ experience of circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non–small cell lung cancer(NSCLC; ref. 1). We congratulate the authors on the quality of their work, which provides an up-to-date reference article about this clinical situation. We particularly appreciate the authors’ efforts in highlighting the choice of early diagnosis strategy to determine the lesions as well as the prognosis. They provided an empirical summary of the ctDNA diagnosis strategies, that is: perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC. We were wondering if the patients could be further grouped according to their perioperative ctDNA level and prognosis to more accurately evaluate the relapse risk (2)To solve this problem, we conducted the ROC curve analysis. The discrimination of ctDNA levels for relapse was evaluated by using the area under the ROC (AUROC) curve. The optimal cut-off point for ROC curves was determined for maximizing the sensitivity and specificity of the ctDNA levels. After calculation, the AUROC curve of hGE levels for preoperative, postoperative 3 days and 1 month were 0.633 (P = 0.002), 0.588 (P = 0.039), and 0.599 (P = 0.020), with cut-off value of 0.973 (sensitivity vs. specificity, 39.7% vs. 87.2%), 0.616(19.0% vs. 98.7%), and 0.169(20.7% vs. 99.1%) ng/mL respectively. The results made us realize that the poor prognosis might be positively correlated with high ctDNA level.We next performed Pearson correlation test to determine the association of perioperative ctDNA values with the duration of tumor relapse. Statistical results revealed that the patients' ctDNA levels were negatively correlated with recurrence-free survival (RFS) duration. The R values were −0.132 (P = 0.286), −0.225 (P = 0.084), and −0.286 (P = 0.021) at preoperative, postoperative 3 days and 1 month.It could be seen that the level of ctDNA showed a certain correlation with the duration of RFS, and this negative correlation became significant at one month postoperatively. Therefore, we suggest that the authors group patients not only on the basis of negative/positive values for ctDNA, but also on the basis of the level of their values in order to classify the relapse risk. In addition, we recommend that for further statistical processing, authors could additionally test ctDNA level at half a year or 1 year after the operation, to further clarify the predictive value of ctDNA level of the duration of RFS.See the Response, p. 3401No disclosures were reported.
Tee-ing up a New Follicular Lymphoma Classification System
Authors: Ari M. Melnick
Journal: Blood Cancer Discovery (2022)

Summary: In this issue of Blood Cancer Discovery, Han and colleagues find that follicular lymphomas (FL) can be stratified into distinct classes with clinical and functional relevance based on their T-cell subset composition. Their findings further indicate that pairing of FL cell MHCII expression with specific T-cell markers may represent a useful diagnostic approach to select patients for particular immunotherapies or immune augmentation therapies independent of genetic profiling. See related article by Han et al., p. 428 (4).
Cancer risk and gammopathies in 2123 adults with Gaucher disease type 1 in the International Gaucher Group Gaucher Registry
Authors: Barry E. Rosenbloom, Maria Domenica Cappellini, Neal J. Weinreb, Marta Dragosky, Shoshana Revel‐Vilk, Julie L. Batista, Davorka Sekulic, Pramod K. Mistry
Journal: American Journal of Hematology (2022)

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.
Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101)
Authors: Hani Babiker, Erkut Borazanci, Vivek Subbiah, Sanjiv Agarwala, Alain Algazi, Jacob Schachter, Michael Lotem, Corinne Maurice-Dror, Daniel Hendler, Shah Rahimian, Hans Minderman, Cara Haymaker, Daruka Mahadevan, Chantale Bernatchez, Ravi Murthy, Rolf Hultsch, Nadia Kaplan, Gregory Woodhead, Charles Hennemeyer, Srinivas Chunduru, Peter M. Anderson, Adi Diab, Igor Puzanov
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors. Patients and Methods: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses. Results: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. Conclusions: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007
Dual antigen–targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia
Authors: Frank Cichocki, Jodie P. Goodridge, Ryan Bjordahl, Sajid Mahmood, Zachary B. Davis, Svetlana Gaidarova, Ramzey Abujarour, Brian Groff, Alec Witty, Hongbo Wang, Katie Tuininga, Behiye Kodal, Martin Felices, Greg Bonello, Janel Huffman, Thomas Dailey, Tom T. Lee, Bruce Walcheck, Bahram Valamehr, Jeffrey S. Miller
Journal: Blood (2022)
The abundance of <i>Ruminococcus bromii</i> is associated with faecal butyrate levels and atopic dermatitis in infancy
Authors: Mari Sasaki, Clarissa Schwab, Alejandro Ramirez Garcia, Qing Li, Ruth Ferstl, Eugen Bersuch, Cezmi A. Akdis, Roger Lauener, Remo Frei, Caroline Roduit
Journal: Allergy (2022)

Impaired microbial development and decreased levels of short chain fatty acids, particularly butyrate, is suggested to have a role in the development of atopic dermatitis (AD).
GIGYF1 disruption associates with autism and impaired IGF-1R signaling
Authors: Guodong Chen, Bin Yu, Senwei Tan, Jieqiong Tan, Xiangbin Jia, Qiumeng Zhang, Xiaolei Zhang, Qian Jiang, Yue Hua, Yaoling Han, Shengjie Luo, Kendra Hoekzema, Raphael A. Bernier, Rachel K. Earl, Evangeline C. Kurtz-Nelson, Michaela J. Idleburg, Suneeta Madan-Khetarpal, Rebecca Clark, Jessica Sebastian, Alberto Fernandez-Jaen, Sara Alvarez, Staci D. King, Luiza L.P. Ramos, Mara Lucia S.F. Santos, Donna M. Martin, Dan Brooks, Joseph D. Symonds, Ioana Cutcutache, Qian Pan, Zhengmao Hu, Ling Yuan, Evan E. Eichler, Kun Xia, Hui Guo
Journal: Journal of Clinical Investigation (2022)

Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. An excess of likely gene-disruptive (LGD) mutations in GIGYF1 was implicated in ASD. Here, we report that GIGYF1 is the second-most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation c.333del:p.L111Rfs*234. Inherited GIGYF1 heterozygous LGD variants were 1.8 times more common than de novo mutations. Among individuals with ASD, cognitive impairments were less likely in those with GIGYF1 LGD variants relative to those with other high-confidence gene mutations. Using a Gigyf1 conditional KO mouse model, we showed that haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments. In contrast, homozygous mice showed more severe social disability as well as cognitive impairments. Gigyf1 deficiency in mice led to a reduction in the number of upper-layer cortical neurons, accompanied by a decrease in proliferation and increase in differentiation of neural progenitor cells. We showed that GIGYF1 regulated the recycling of IGF-1R to the cell surface. KO of GIGYF1 led to a decreased level of IGF-1R on the cell surface, disrupting the IGF-1R/ERK signaling pathway. In summary, our findings show that GIGYF1 is a regulator of IGF-1R recycling. Haploinsufficiency of GIGYF1 was associated with autistic behavior, likely through interference with IGF-1R/ERK signaling pathway.
Vitamin D receptor and STAT6 interactome governs oesophageal epithelial barrier responses to IL-13 signalling
Authors: Michael Brusilovsky, Mark Rochman, Tetsuo Shoda, Michael Kotliar, Julie M Caldwell, Lydia E Mack, John A Besse, Xiaoting Chen, Matthew T Weirauch, Artem Barski, Marc E Rothenberg
Journal: Gut (2022)

Objective The contribution of vitamin D (VD) deficiency to the pathogenesis of allergic diseases remains elusive. We aimed to define the impact of VD on oesophageal allergic inflammation. Design We assessed the genomic distribution and function of VD receptor (VDR) and STAT6 using histology, molecular imaging, motif discovery and metagenomic analysis. We examined the role of VD supplementation in oesophageal epithelial cells, in a preclinical model of IL-13-induced oesophageal allergic inflammation and in human subjects with eosinophilic oesophagitis (EoE). Results VDR response elements were enriched in oesophageal epithelium, suggesting enhanced VDR binding to functional gene enhancer and promoter regions. Metagenomic analysis showed that VD supplementation reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications (H3K27Ac) induced by IL-13 in VD-deficient cells, including genes encoding the transcription factors HIF1A and SMAD3 , endopeptidases ( SERPINB3 ) and epithelial-mesenchymal transition mediators ( TGFBR1, TIAM1, SRC, ROBO1, CDH1 ). Molecular imaging and chromatin immunoprecipitation showed VDR and STAT6 colocalisation within the regulatory regions of the affected genes, suggesting that VDR and STAT6 interactome governs epithelial tissue responses to IL-13 signalling. Indeed, VD supplementation reversed IL-13-induced epithelial hyperproliferation, reduced dilated intercellular spaces and barrier permeability, and improved differentiation marker expression (filaggrin, involucrin). In a preclinical model of IL-13-mediated oesophageal allergic inflammation and in human EoE, VD levels inversely associated with severity of oesophageal eosinophilia and epithelial histopathology. Conclusions Collectively, these findings identify VD as a natural IL-13 antagonist with capacity to regulate the oesophageal epithelial barrier functions, providing a novel therapeutic entry point for type 2 immunity-related diseases.